1. Field of the Invention
The invention relates to a biological delivery system, and more specifically to a glutathione-based delivery system.
2. Description of the Related Art
The blood brain barrier (BBB) is composed of brain endothelial cells capable of blocking foreign substances, such as toxins, due to the tight junctions therebetween. Hydrophobic or low-molecular-weight molecules, however, can pass through the BBB via passive diffusion.
Nevertheless, active compounds, such as hydrophilic protein drugs for treating cerebral or nervous diseases and analgesic peptide drugs acting on the central nervous system, cannot enter brain tissue thereby due to large molecular weight or hydrophilicity, resulting in decomposition thereof by enzymes.
Current research has developed various methods of allowing active compounds to pass through the BBB, including structural modification to increase hydrophobicity of drugs, absorption-mediated transport (AMT) allowing positive-charged carriers to pass via charge absorption, carrier-mediated transcytosis (CMT) allowing hydrophilic metal ions such as Na+ and K+, di-peptides, tri-peptides or glucose to pass via transporters, and receptor-mediated transcytosis (RMT) allowing macro molecules such as insulin, transferrin, or low-density lipoprotein (LDL) to pass via transcytosis.
Glutathione (GSH) is an endogenous antioxidant. If concentration thereof in serum is insufficient, some nervous diseases, such as chronic fatigue syndrome (CFS), may occur.
In 1988, Kiwada Hiroshi provided a liposome capable of accumulation in liver comprising a N-acylglutathione such as N-palmitoylglutathione and a phospholipid such as phosphotidylcholine to target and treat liver diseases recited in JP63002922.
In 1994, Berislav V. Zlokovic asserted that glutathione (GSH) reaches and passes through the BBB of a guinea pig via a special route, such as GSH-transporter, without decomposition.
In 1995, Berislav V. Zlokovic asserted that glutathione (GSH) exists in brain, astrocyte and endothelial cells in millimolar concentration.
In 1995, Ram Kannan asserted that GSH uptake depends on Na+ concentration. If Na+ concentration is low, GSH uptake from brain endothelial cells may be inhibited. Hie also pointed Na-dependent GSH transporter located on the luminal side of the BBB manages GSH uptake and Na-independent GSH transporter located on the luminal side of the BBB manages efflux of GSH. Additionally, Kannan constructed a rat hepatic canalicular GSH transporter (RcGSHT) system using the brains of mice and guinea pigs to analyze cDNA fragments 5, 7, and 11. The results indicate that fragment 7 represents Na-dependent GSH transporter and fragments 5 and 11 represent Na-dependent GSH transporter.
In 1999, Ram Kannan built a mouse brain endothelial cell line (MBEC-4) model simulating BBB situation. The model proved that Na-dependent GSH transporter is located on the luminal side of the MBEC-4 cell.
In 2000, Ram Kannan asserted that GSH passes through the BBB via Na-dependent GSH transporter in human cerebrovascular endothelial cells (HCBC) and Na-dependent GSH transporter exists in the luminal plasma membrane of HCEC.
In 2003, Zhao Zhiyang provided an anti-cancer pro-drug bonded with glutathione s-transferase (GST)/glutathione (GSH) by sulfonamide covalent bonds to target and treat specific cancer cells after break of the sulfonamide bonds recited in US2003109555. This modification can protect amino groups of drugs, increase solubility thereof, and alter absorption and distribution thereof in body.
Additionally, various opioid-peptide secreted by cerebrum have been separated such as enkephalin, endomorphin-1, and endomorphin-2. These natural analgesics, acting on opioid receptors, have lower habituation and respiratory depression than morphine. However, such drugs cannot pass through the BBB due to low-stability in plasma. Delivery to the cerebrum can only be accomplished by intracerebroventricular injection or intrathecal injection.
Thus, administration of analgesic peptide drugs is desired preventing decomposition by enzymes and prolonging the analgesic effect thereof.